Fig. 1.

The PKA R1α system and disease-related mutations. (A) Domain organization of PKA R1α with non-haploinsufficient CNC and ACRDYS1 mutants within the tandem cAMP-binding domains (CBDs) indicated in green and red, respectively. The blue star in CBD-A denotes Ala-211, which is mutated to Asp in CNC and to Thr in ACRDYS1, and in CBD-B denotes Gly-287, which is mutated to Trp in CNC and to Glu in ACRDYS1. Further details are available in SI Appendix, Fig. S1A. (B) Structure of R1α CBDs in the cAMP-bound state [dark colors; PDB: 1RGS (26)] and C-subunit-bound state [light colors; PDB: 2QCS (5)]. CNC and ACRDYS1 mutation sites are highlighted with green and red spheres, while cAMP is shown with black sticks. The N3A motif (αN-helix, 3₁₀-loop, and αA helix) and phosphate binding cassette (PBC) are highlighted in red and yellow, respectively, while the rest of CBDs is in cyan. The Insets show details of the cAMP-binding sites adjacent to the A211 and G287 mutations, with selected hydrogen bonds and capping interactions highlighted by dashed lines and surfaces.